Profiles of BBDC Members Primarily Involved In Diabetes Research

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Kilkenny, Dawn M. - PhD

University of Toronto Appointment(s): Associate Director - Undergraduate (IBBME)
Lecturer (IBBME)
Institute of Biomaterials and Biomedical Engineering (IBBME); and Department of Medicine

Other Appointment(s):  
 

Contact Information:
Room 407 Rosebrugh
164 College Street
Toronto, ON   M5S 3G9

Phone: (416) 978-8835
Fax: (416) 978-4317
Email: dawn.kilkenny@utoronto.ca
Websites: http://www.ibbme.utoronto.ca/faculty/members/kilkenny/

Diabetes Related Research Activities:

My research interest is focused on Fibroblast Growth Factor receptor (FGFR) expression and signaling in adult beta cells. We have identified control of FGFR1-expression and -signaling by modifications in the beta-cell extracellular microenvironment. We are now investigating the role of the novel kinase-deficient FGFR5 isoform in the regulation of beta-cell FGFR1-signalling. Using insulin-secreting cell lines, we have expression of FGFR5 at both the cell membrane as well as in association with insulin secretory granules. Expression of FGFR5 enhances classical intracellular FGF-mediated signaling pathways, cellular matrix adhesion as well as insulin content. Expression of a 'dominant-negative' (kinase-deficient) isoform of classical FGFR1 (similar in structure to FGFR5) has been shown to induce a diabetic phenotype in mice. Taken together, these data promote our interest in defining the role that FGFRs play in normal beta-cell maintenance and insulin secretion. We currently examine this receptor signaling system using methods of fluorescence microscopy (live-cell and fixed) both in vitro as well as in vivo (whole islet), and verify our results in combination with traditional biochemical techniques.

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Klip, Amira

University of Toronto Appointment(s): Professor, Department of Paediatrics; Department of Biochemistry; and Department of Physiology

Other Appointment(s): Senior Scientist, The Hospital For Sick Children

Contact Information:
The Hospital for Sick Children
555 University Ave., McMaster Building, Room 5004
Toronto, ON   M5G 1X8

Phone: (416) 813-6392
Fax: (416) 813-5028
Email: amira@sickkids.ca
Websites: http://www.sickkids.ca/AboutSickKids/Directory/People/K/Amira-Klip-staff-profile.html

Diabetes Related Research Activities:

We study how insulin stimulates glucose entry into muscle and how this fails in insulin resistance and type 2 diabetes. We explore insulin signals, movement of vesicles containing glucose transporter 4 (GLUT4) and strategies to render muscle cells insulin-resistant. We generated platforms of muscle cells in culture expressing tagged GLUT4 and a number of insulin signals, as well as transgenic mice expressing tagged GLUT4 in muscle, to test GLUT4 movement in vivo. With these systems we found that signals downstream of PI3-kinase bifurcate into activation of Akt and of the small G protein Rac. Downstream of Akt lies AS160 that regulates the small G proteins Rab8A and Rab13 to control GLUT4 vesicle arrival near the membrane. GLUT4 vesicles arriving at the plasma membrane (in the TIRF-imaging zone) then tether to actin filaments through the molecular motor Myosin 1c. In turn, Rac controls actin filament remodelling, crucial for GLUT4 vesicle translocation to the membrane, and our collaborator Erik Richter (Copenhagen) found that mice lacking Rac in muscle become insulin-resistant. Moreover, overexpressing Rac in cells overcame insulin resistance.

 

Recently we discovered that the saturated fatty acid palmitate renders macrophages inflammatory, to produce cytokines that make muscle cells insulin-resistant. Moreover, direct activation of the NOD innate immunity recognition receptors, in cells or in vivo, caused insulin resistance. Finally, we documented a particular infiltration of inflammatory macrophages in the muscles of high fat-fed mice and of obese, insulin-resistant humans. These collective findings contribute to our understanding of the link between inflammation and insulin resistance.

 

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Kohly, Radha P. - MD, PhD, FRCSC

University of Toronto Appointment(s): Assistant Professor, Department of Ophthalmology and Vision Sciences

Other Appointment(s): Eye Physician and Surgeon and Medical Retina Specialist, Sunnybrook Health Sciences Centre

Contact Information:
Sunnybrook Health Sciences Centre
2075 Bayview Ave., Room M1202b
Toronto, ON   M4N 3M5

Phone: (416) 480-5607
Fax: (416) 480-5675
Email: radha.kohly@sunnybrook.ca

Diabetes Related Research Activities:

My current research interest is in retinal vascular diseases including diabetic macular edema. We have demonstrated the importance of serum biomarkers in the role of diabetic retinopathy. Currently, we are measuring cytokines drawn from the aqueous humor in patients with diabetic macular edema to determine if they can predict responses to treatment with intravitreal lucentis injections. The goal of this research is to ultimately use aqueous humor cytokines to guide treatment decisions with various intravitreal medications including anti-VEGF agents, and steroids, in the management of diabetic macular edema.

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Konvalinka, Ana - MD, PhD, FRCPC

University of Toronto Appointment(s): Assistant Professor, University of Toronto
Associate Member, Institute of Medical Science

Other Appointment(s): Transplant Nephrologist, Department of Medicine, Division of Nephrology, University Health Network
Scientist, Toronto General Hospital Research Institute
Associate Staff, Division of Nephrology, Mount Sinai Hospital

Contact Information:
Toronto General Hospital
585 University Avenue, 11-PMB-189
Toronto, ON   M5G 2N2

Phone: (416) 340-6950
Fax: 1-888-247-8594
Email: ana.konvalinka@uhn.ca

Diabetes Related Research Activities:

My research program has three projects directly related to diabetes:

1) Angiotensin II is a peptide produced in the kidney that leads to progression of diabetic kidney disease. We have identified a group of proteins regulated by angiotensin II in kidney cells and demonstrated that these proteins were involved in kidney fibrosis. We have also demonstrated that measurements of these proteins in urine correlate with kidney fibrosis. We are now studying the mechanisms of regulation of these angiotensin II-activity proteins. Agents that inhibit these proteins may represent new potential treatments of diabetic and other kidney diseases.

2) The mechanisms leading to development of early diabetic nephropathy are still poorly understood. By studying the urinary peptidome of patients with juvenile diabetes mellitus type I and no known diabetic complications, we have identified several peptides of protein uromodulin. We are now investigating the potential function of these peptides and proteases that cleave them from uromodulin, in order to enhance our understanding of the early events leading to kidney injury in type I diabetes.

3) Male sex has been associated with increased risk of progression of kidney disease. We have recently discovered that male sex hormones affect metabolic enzymes in kidney cells and may result in maladaptive metabolic changes in the kidney. These effects were demonstrated in two different animal models of diabetes, where male animals had increased expression of these enzymes and increased kidney hypertrophy and oxidative stress. We are now investigating how sex hormones affect metabolism in kidney cells and whether we can modify the maladaptive effects of testosterone through manipulation of metabolism.

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Kramer, Caroline - MD, PhD

University of Toronto Appointment(s): Assistant Professor, Department of Medicine, Division of Endocrinology and Metabolism

Other Appointment(s): Clinician-Scientist, Mount Sinai Hospital

Contact Information:
Leadership Sinai Centre for Diabetes
60 Murray Street, Suite L5-029
Toronto, ON   M5T 3L9

Phone: (416) 586-4800
Email: caroline.kramer@sinaihealthsystem.ca

Diabetes Related Research Activities:

My clinical research focuses on (i) the impact of obesity on metabolic dysfunction, (ii) the pathophysiology and risk factors for the development of type 2 diabetes mellitus (T2DM), (iii) risk factors for cardiovascular disease in individuals with metabolic abnormalities, and (iv) strategies for the treatment of T2DM. I am particularly interested in understanding the pathophysiology of T2DM in individuals with various degrees of obesity and differential patterns of body fat distribution.

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